Currently, imaging, fecal immunochemical tests (FITs) and serum carcinoembryonic antigen (CEA) tests are not adequate for the early detection and evaluation of metastasis and recurrence in colorectal cancer (CRC). To comprehensively identify and validate more accurate noninvasive biomarkers in urine, we implement a staged discovery-verification-validation pipeline in 657 urine and 993 tissue samples from healthy controls and CRC patients with a distinct metastatic risk. The generated diagnostic signature combined with the FIT test reveals a significantly increased sensitivity (+21.2% in the training set, +43.7% in the validation set) compared to FIT alone. Moreover, the generated metastatic signature for risk stratification correctly predicts over 50% of CEA-negative metastatic patients. The tissue validation shows that elevated urinary protein biomarkers reflect their alterations in tissue. Here, we show promising urinary protein signatures and provide potential interventional targets to reliably detect CRC, although further multi-center external validation is needed to generalize the findings.
Esophageal squamous cell carcinoma (ESCC) is one of the fatal malignancies worldwide. It has an increased propensity to metastasize via lymphogenous routes in an early stage. The prognosis of patients with lymph node metastases (LNM) is often worse than that of patients without metastases. Although several factors have been found to influence metastasis, the mechanisms of preference for specific metastatic routes remain poorly understood. Herein, we provide evidence that the intrinsic hypersensitivity of tumor cells to ferroptosis may proactively drive lymphatic metastasis. Serum autoantibodies associated with LNM of early ESCC were screened using a whole-proteome protein array containing 19 394 human recombinant proteins, and an anti-BACH1 autoantibody was first identified. Pan-cancer analysis of ferroptosis-related genes with preferential lymphatic metastasis and preferential hematogenous metastasis based on The Cancer Genome Atlas data was performed. Only BACH1 showed significant overexpression in tumors with preferential lymphatic metastasis, whereas it was downregulated in most tumors with preferential nonlymphatic metastasis. In addition, it was found that the serum levels of autoantibodies against BACH1 were elevated in early-stage patients with LNM. Interestingly, BACH1 overexpression and ferroptosis induction promoted LNM but inhibited hematogenous metastasis in mouse models. Transcriptomic and lipidomic analyses found that BACH1 repressed SCD1-mediated biosynthesis of monounsaturated fatty acids, especially oleic acid (OA). OA significantly attenuated the ferroptotic phenotypes and reversed the metastatic properties of BACH1-overexpressing cells. OA addition significantly rescued the ferroptotic phenotypes and reversed the metastatic properties of BACH1-overexpressing cells. Importantly, the concentration gradient of OA between primary lesions and the lymph resulted in the chemoattraction of tumor cells to promote invasion, thus facilitating lymphatic metastasis. BACH1-induced ferroptosis drives lymphatic metastasis via the BACH1-SCD1-OA axis. More importantly, this study confirms that ferroptosis is a double-edged sword in tumorigenesis and tumor progression. The clinical application of ferroptosis-associated agents requires a great caution.
Background Emerging evidence indicates that myristoylated alanine‐rich C kinase substrate like 1 (MARCKSL1) is involved in the progression of esophageal squamous cell carcinoma (ESCC). However, the underpinning mechanism is unclear. Here, we investigated the mechanisms involving MARCKSL1 in ESCC progression. Methods CCK8, Transwell and wound‐healing assays were employed to test the effect of MARCKSL1 on proliferation, invasion and migration in vitro. Next, transcriptome profiling was conducted through RNA sequencing to reveal the underlying mechanism of MARCKSL1 in ESCC progression, which was subsequently verified by western blot and qPCR analysis. Moreover, immunofluorescence and gelatin degradation assays were performed to reveal the ability of MARCKSL1 to mediate invadopodia formation and extracellular matrix (ECM) degradation. Finally, the correlation between MARCKSL1 and the clinicopathological features of ESCC patients was assessed based on TCGA database analysis and immunohistochemistry staining of tissue microarrays. Results Knockdown of MARCKSL1 markedly attenuated the cell motility capacity of ESCC cells in vitro, while MARCKSL1 overexpression had the opposite effect. Transcriptomic analysis showed that MARCKSL1 mediated the mobility and migration of ESCC cells. In addition, overexpression of MARCKSL1 increased the colocalization of F‐actin and cortactin at the frontier edge of migrating cells and ECM degradation. Furthermore, in ESCC patients, the mRNA level of MARCKSL1 in esophageal carcinomas ( n = 182) was found to be notably higher than that in adjacent esophageal epithelia ( n = 286) and the expression levels of MARCKSL1 in the tumor tissues ( n = 811) were significantly increased compared to those in noncancerous esophageal tissues ( n = 442) with a large sample size. Higher expression of MARCKSL1 was positively correlated with lymph node metastasis and associated with worse survival rates of patients with ESCC. Conclusion MARCKSL1 promotes cell migration and invasion by interacting with F‐actin and cortactin to regulate invadopodia formation and ECM degeneration. High MARCKSL1 expression is positively correlated with poor prognosis in ESCC patients with lymph node metastasis.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.